import/export and exchange rxn missing for dihydroorotate

[johan-gson]

Description of the issue:

The metabolite (S)-dihydroorotate[c] is reported to be exported by cells (see https://www.nature.com/articles/s41467-018-08033-9 ), but there is no export rxn (and I assume there should be an import rxn as well). There is no exch rxn either. I have no idea about GPR though. This is happening in hypoxia.

Expected feature/value/output:

Just add the reactions I'm thinking, i.e.
(S)-dihydroorotate[c] <=> (S)-dihydroorotate[s]
(S)-dihydroorotate[s] <=>

Current feature/value/output:

Reproducing these results:

I hereby confirm that I have:

• Tested my code on my own computer for running the model
• Done this analysis in the main branch of the repository
• Checked that a similar issue does not exist already

[JonathanRob]

Thanks for spotting this. Though I guess now we would abbreviate the compartment as [e] rather than [s].

[mihai-sysbio]

Looking a bit more into this, the annotation for these reactions doesn't look straightforward.

A name search for (S)-dihydroorotate returned CHEBI:30864, but that is different from CHEBI:17025 which is the annotation of MAM00180c. In fact, the CHEBI name for MAM00180c is (S)-dihydroorotic acid.

Overlooking the potentially misannotated metabolite, some transport reactions for (S)-dihydroorotate seem to exist in MNX.

[johan-gson]

Yeah, it is with this for many compounds, that you can either talk about the ion or the acid (which includes the H+). It is the same with for example the amino acid glutamate/glutamic acid

[edkerk]

Thanks, this was a real gap. (S)-dihydroorotate (MAM00180, KEGG C00337) existed only in the cytosol, so the model could not reproduce its secretion under hypoxia (PMID:30643150). The extracellular form plus transport and exchange are now added, using [e] as suggested.

New ID	Type	Reaction
MAM00180e	metabolite	(S)-dihydroorotate in the extracellular compartment
MAR20193	transport	(S)-dihydroorotate[c] <=> (S)-dihydroorotate[e]
MAR20194	exchange	(S)-dihydroorotate[e] <=>

Both reactions are reversible, so import and export both work. The transport carries no GPR, since there is no established plasma-membrane transporter for dihydroorotate; if a specific carrier is identified it can be added later.

On the annotation point: MAM00180 carries CHEBI:17025 (the acid) rather than CHEBI:30864 (the anion). That is the general ion-versus-acid convention across the model rather than something specific to this metabolite, so it is left unchanged here instead of fixing one case in isolation.